In the elderly, there is a significant decline in both cellular and humoral immunity, leading to a state of dysregulated immune functions, or immunosenescence. Immunosenescence compromises protection against infectious diseases and contributes to the increased susceptibility of the elderly to infection. Furthermore, immunosenescence is responsible for the diminished responsiveness of the elderly to vaccination. Thus, the elderly are particularly vulnerable and are at greater risk in the event of a bioterror attack. An impaired response to influenza virus infection and vaccination in the elderly may be clinically most relevant. The responses to influenza vaccination are significantly impaired in aged people. Both primary and secondary antibody responses to influenza vaccination are diminished in the elderly. Even when the antigenic match between influenza vaccine and circulating virus is close, vaccination provides protection for only 30%- 40% of subjects aged >= 65 years, compared with 70-90% of those aged <65 years. The currently available trivalent inactivated influenza vaccines are particularly ineffective in preventing deaths among elderly persons with associated chronic conditions, underscoring the need for influenza vaccines that are more effective in elderly persons who need them most. Fc receptors (FcR) link the humoral and cellular branches of the immune system and have crucial functions in the activation and modulation of immune responses. Our recent studies indicate that immunization with immune complexes (IC) can correct the age-related deficiency in humoral and cellular immune responses to model antigens as well as influenza vaccines in mice. We have also demonstrated that the inhibitory Fc receptor, Fcgamma IIB, can be selectively ablated by RNA interference using small interfering RNA (siRNA). Thus, manipulating FcR signaling and vaccination with IC may constitute a novel immunization strategy to provide effective protection to immune compromised elderly population against influenza infection. In this project, we propose the following specific aims: Aim 1. Determine the mechanisms by which immune responses are regulated by IC Aim 2. Study the modulation of immune responses by selective signaling Fc receptors Aim 3. Determine the effectiveness of 1C vaccines in overcoming age-related immune deficiency.